کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6272470 | 1614781 | 2015 | 12 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice Fibrillin-1 impairment enhances blood-brain barrier permeability and xanthoma formation in brains of apolipoprotein E-deficient mice](/preview/png/6272470.png)
- Dysfunctional fibrillin-1 impairs blood-brain barrier integrity.
- Peripheral leukocyte infiltration further degrades the blood-brain barrier.
- Accordingly, lipoproteins can enter the brain, resulting in xanthoma formation.
We recently reported that apolipoprotein E (ApoE)-deficient mice with a mutation in the fibrillin-1 gene (ApoEâ/âFbn1C1039G+/â) develop accelerated atherosclerosis with enhanced inflammation, atherosclerotic plaque rupture, myocardial infarction and sudden death. In the brain, fibrillin-1 functions as an attachment protein in the basement membrane, providing structural support to the blood-brain barrier (BBB). Here, we investigated whether fibrillin-1 impairment affects the permeability of the BBB proper and the blood-cerebrospinal fluid barrier (BCSFB), and whether this leads to the accelerated accumulation of lipids (xanthomas) in the brain. ApoEâ/â (n = 61) and ApoEâ/âFbn1C1039G+/â (n = 73) mice were fed a Western-type diet (WD). After 14 weeks WD, a significantly higher permeability of the BBB was observed in ApoEâ/âFbn1C1039G+/â mice compared to age-matched ApoEâ/â mice. This was accompanied by leukocyte infiltration, enhanced expression of pro-inflammatory cytokines, matrix metalloproteinases and transforming growth factor-β, and by decreased expression of tight junction proteins claudin-5 and occludin. After 20 weeks WD, 83% of ApoEâ/âFbn1C1039G+/â mice showed xanthomas in the brain, compared to 23% of their ApoEâ/â littermates. Xanthomas were mainly located in fibrillin-1-rich regions, such as the choroid plexus and the neocortex. Our findings demonstrate that dysfunctional fibrillin-1 impairs BBB/BCSFB integrity, facilitating peripheral leukocyte infiltration, which further degrades the BBB/BCSFB. As a consequence, lipoproteins can enter the brain, resulting in accelerated formation of xanthomas.
Journal: Neuroscience - Volume 295, 4 June 2015, Pages 11-22